Reduced blood pressure of CFTR-F508del carriers correlates with diminished arterial reactivity rather than circulating blood volume in mice.
Reduced blood pressure of CFTR-F508del carriers correlates with diminished arterial reactivity rather than circulating blood volume in mice.
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DOI：
10.1371/journal.pone.0096756
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Roghair RD
中科院分区：
文献类型：
--
作者：
Peotta VA;Bhandary P;Ogu U;Volk KA;Roghair RD
囊性纤维化跨膜传导调节因子（CFTR）的F508del突变是囊性纤维化（CF）最常见的原因。CF患者和F508del携带者血压均下降。虽然这被归因于盐的消耗，但最近的研究表明F508del的表达干扰了平滑肌细胞钙的动员。我们检验了F508del突变携带者在没有减少循环血容量的情况下具有较低的成人血压和主动脉收缩性降低的假设。通过无线电遥测，F508del杂合小鼠的动脉压明显低于野生型C57BL/6对照组，在黑暗到光明周期转变时效果最大（平均差为10 mmHg）。为了复制交感神经兴奋对血管的影响，异丙肾上腺素和肾上腺素同时输注，F508del小鼠的动脉压再次显著降低。从F508del杂合小鼠分离的主动脉对去甲肾上腺素的收缩明显降低（0.9±0.2 mN比2.9±0.7 mN）。野生型CFTR或肌醇三磷酸受体的抑制复制了F508del主动脉的表型。CFTR携带者状态不改变循环血容量。我们得出结论，CFTR-F508del突变降低了主动脉收缩性并降低了动脉压。作为camp激活的氯离子通道，促进钙的动员，我们推测野生型CFTR在肾上腺素能受体刺激时的协同激活可以缓冲儿茶酚胺对血管的舒张反应，而这种代偿性血管收缩张力的丧失可能导致CFTR- f508del突变杂合子携带者的动脉压降低。
The F508del mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common cause of cystic fibrosis (CF). Both CF patients and F508del carriers have decreased blood pressure. While this has been attributed to salt depletion, recent studies have shown F508del expression interferes with smooth muscle cell calcium mobilization. We tested the hypothesis that carriers of the F508del mutation have lower adult blood pressures and reduced aortic contractility without a reduction in circulating blood volume. By radiotelemetry, F508del heterozygous mice had significantly lower arterial pressures than wild-type C57BL/6 controls, with the greatest effect seen at the time of dark-to-light cycle transition (mean difference of 10 mmHg). To replicate the vascular effects of sympathetic arousal, isoproterenol and epinephrine were co-infused, and F508del mice again had significantly reduced arterial pressures. Aortas isolated from F508del heterozygous mice had significantly decreased constriction to noradrenaline (0.9±0.2 versus 2.9±0.7 mN). Inhibition of wild-type CFTR or the inositol triphosphate receptor replicated the phenotype of F508del aortas. CFTR carrier status did not alter circulating blood volume. We conclude the CFTR-F508del mutation decreases aortic contractility and lowers arterial pressures. As a cAMP-activated chloride channel that facilitates calcium mobilization, we speculate wild-type CFTR co-activation during adrenergic receptor stimulation buffers the vasodilatory response to catecholamines, and loss of this compensatory vasoconstrictor tone may contribute to the lower arterial pressures seen in heterozygote carriers of a CFTR-F508del mutation.
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影响因子：
4.5
作者：
Divangahi M;Balghi H;Danialou G;Comtois AS;Demoule A;Ernest S;Haston C;Robert R;Hanrahan JW;Radzioch D;Petrof BJ
通讯作者：
Petrof BJ
影响因子：
3.6
作者：
Haskell, Sarah E.;Hermann, Gregory M.;Reinking, Benjamin E.;Volk, Kenneth A.;Peotta, Veronica A.;Zhu, Vivian;Roghair, Robert D.
通讯作者：
Roghair, Robert D.
影响因子：
3.6
作者：
Mock DM;Mock NI;Lankford GL;Burmeister LF;Strauss RG;Widness JA
通讯作者：
Widness JA
影响因子：
37.8
作者：
Makino, M;Hayashi, H;Ebihara, S
通讯作者：
Ebihara, S
DOI：
10.1016/j.bbadis.2011.08.008
发表时间：
2011-11-01
影响因子：
6.2
作者：
Martins, Joana Raquel;Kongsuphol, Patthara;Kunzelmann, Karl
通讯作者：
Kunzelmann, Karl